Combined antiretroviral treatment (c-ART) has greatly improved the outcome of HIV infection. The key objective of c-ART is to suppress viral replication and to induce the production of sufficient numbers of CD4+ T-cells to prevent AIDS-defining (CD4+ T-cell counts below 200 cells/mm3), and/or non-AIDS-defining (CD4+ T-cell counts below 500 cells/mm3) severe events from occurring (1). Immunological failure is defined as an inability to reach these levels of CD4+ T cells on c-ART. In large cohort of patients displaying viral suppression, immunological success seemed to be largely time-dependent, as the number of CD4+ T-cells seemed to increase steadily, even after seven years (2). CD4+ T-cell restoration may be impeded by mechanisms related to HIV infection and its consequences, or modulated by host factors, both of which may affect T-cell homeostasis either in the periphery or at the level of T-cell production. Demographic factors (age, sex, ethnic group (3-5)) affect CD4+ T-cell levels and, thus, immune restoration. The characteristics of HIV infection in the patient (CD4+ T-cell nadir, peak viral load, duration of infection and viral control on c-ART (4, 6-8)) are also key determinants of CD4+ T-cell recovery. Increases in immune activation (9, 10) and inflammation (11, 12) are currently considered to be the principal mechanisms underlying poor immunological responses on c-ART. Such alterations affect the homeostasis of the T-cell pool, modifying both peripheral and thymic T-cell levels (13). Specific host genetic factors, including polymorphisms of genes of the inflammation/apoptosis pathway (14) or genes involved in T-cell development, such as IL7R (15), have also been associated with poor CD4+ T-cell recovery.
Several studies have shown that HIV may affect CD34+ cells before their colonization of the thymus to generate T lymphocytes (16-18). It remains unclear whether these cells are directly infected (18-24), but it is widely thought that the virus affects the microenvironment of the precursors and stromal cells supporting the architecture of the site (16, 17, 25, 26). Many studies have linked the persistent disturbance of the CD34+ cells by HIV to a decrease in their intrinsic clonogenic potential in humans (17, 20, 25, 27-35) and simian models of infection (26, 36-38). Some of these studies analyzed T-cell development during HIV infection (30, 31, 37-39), but only a few addressed this issue in the context of incomplete immune restoration (17, 34), and none of these studies considered a specific impairment of T-cell development.